Ethynylated quinolizinium



United States Patent 4 Claims. (Cl. 260286) This is a divisional application of our copending application Serial No. 323,896, filed on November 15, 1963 now U.S. Patent No. 3,261,839.

This invention relates to substituted quinolizines. More particularly, this invention relates to certain ethynylated quinolizines having the formula:

wherein R and R may be hydrogen, hydroxy or lower alkoxy such as methoxy, ethoxy, propoxy, and the like; R may be hydrogen or lower alkyl such as methyl, ethyl, propyl, butyl, isobutyl and the like; R, may be hydrogen or an acyl radical such as acetyl, propionyl, benzoyl and the like; and R may be hydrogen, halogen such as chlorine or bromine, lower alkoxy such as methoxy or ethoXy, or lower alkyl such as methyl, ethyl, propyl and the like, or an aryl radical such as phenyl, benzyl and the like; and n is an integer of 1 or 2. This invention also includes within its scope a novel process for the production of these quinolizines as Well as intermediates useful for their production. The use of a Wiggly line in the above formula denotes that the orientation of hydrogen atom can be either cisor trans-orientated with respect to R On the other hand, the use of a dotted line denotes trans-orientation and the use of a solid line denotes cisorientation.

The novel compounds of this invention are related to the cyclopentanophenanthrenes and are important therapeutic agents useful in the treatment of circulatory collapse and endocrine disorders.

In addition the novel compounds of this invention are valuable intermediates for the production of other substituted quinolizines such as those of the formula:

lower alkoxy- 3,314,962 Patented Apr. 18, 1967 which can be readily obtained by reducing the novel 1- ethynylated quinolizines of this invention wherein R is hydrogen and R is lower alkoxy employing reducing agents such as sodium or potassium in solvents such as liquid ammonia.

In accordance with this invention, the compounds of this invention are produced by ring closing ethynylated lactams of the formula:

by reaction with an agent such as phosphorous oxychloride and the like.

The ethynylated lactams employed as starting material are described and claimed in our copending application, Serial No. 304,976 filed August 27, 1963, now U.S. Patent No. 3,219,668.

The starting materials for these ethynylated lactams are keto lactams of Formula V below. These are prepared from R, and R substituted phenylalkylamines of the general Formula III below and substituted ketoacids of the general Formula IV below in accordance with the process described in our copending application Serial No. 318,190, filed October 23, 1963. The R and R substituted phenylalkylamines such as 3,4-diethoxyphenylethylamines are well known compounds which are de scribed in the literature, for example in Chemical Abstracts, vol. 56, page 10006 and by Ide et al. in J.A.C.S., vol 59, page 726 (1937). The ketoacids of Formula IV are prepared according to the process described in our copending application Serial No. 310,146, filed September 19, 1963, using 2-R -cycloalkane-1,3-diones as starting material. Such 2-R -cycloalkane-1,3-diones are Well known in the art and may be prepared according to the procedure of Panouse and Sannie published in Bull Soc. Chim. France, 1955, page 1036. See also H. Smith, JCS. 1964, page 4472.

Fhe keto lactam V is then treated with acetylene or R .ubstituted acetylene such as chloroor methoxyacetylene form the ethynylated lactams in accordance with the )rocess set forth in US. Patent No. 3,219,668.

The ring closure reaction is generally carried out by 'efiuxing the reactants in an inert solvent such as xylene, oluene or benzene for a period of 10 to 45 minutes to Form a substituted quinolizine containing a quaternary ritrogen and having the formula:

The above compound is then reduced to one having :ertiary nitrogen by treatment with a complex alkali metal iydride in an inert solvent such as methanol, ethanol and :he like. Suitable complex alkali metal hydrides for this reduction are, for example, potassium borohydride or solium borohydride. The reaction product is recovered by removal of the solvent in vacuo.

The following examples are included in order further to illustrate the invention. All temperatures are given in degree centigrade.

EXAMPLE 1 Cis-1,2,3,3a,5,6,10b,11,12,12adecahydr0 1 hydroxy-lethynyl 8 methoxy-I2a-methylbenz0[a]cyclopenlafi] quinolizine hydrobromide A solution of 4.35 grams of cis-octahydro-1-m(rnethoxyphenethyl) 4a methyl 5 hydroxy 5 ethynyl- ZH 1 pyrindine 2 one in 100 ml. of benzene and ml. of phosphorous oxychloride is refluxed for minutes. The reaction mixture is concentrated to an oil under reduced pressure. The oil is dissolved in 300 ml. of ethanol and 5 grams of sodium borohydride added in portions over a period of one half hour. The mixture is stirred for one half hour more, diluted with 200 ml. of water and the total reaction mixture concentrated to dryness. The residue is partitioned between ether and water and the ether solution dried over magnesium sulfate. Dry hy- :lrogen bromide is passed into the ether solution to give an oily precipitate. The oil is taken up in 10 ml. of methanol and cooled to 0 for about 16 hours to yield :is-1,2,3,3a,5,6,10b,11,12,12a decahydro 1 hydroxy- 1 ethynyl 8 methoxy 12a methylbenzo[a]cyclopenta[f]quinolizine hydrobromide as white crystals. The product is recrystallized from methanol to give a melting point of 237.9.

EXAMPLE 2 Trans-1,2,3,3a,5,6,10b,]1,12,12a-decahydro 1 hydroxyethynyl 8 methoxy 12a methylbenz0[a]cycl0- pen ta [1'] quinolizine In the same way as described in Example 1, 15.5 grams of trans-octahydro 1 (m-methoxyphenethyl) 4a methyl 5 hydroxy 5 ethynyl 2H 1 pyrindine 2 one gives, on cyclization with 50 m1. phosphorous oxychloride in 600 ml. of benzene followed by reduction with 15 grams of potassium borohydride, trans-1,2,3,3a,5,6, 10b,11,12,12a decahydro 1 hydroxy 1 ethynyl 8 methoxy 12a methylbenzo[a]cyclopenta[f]quinolizine as white crystals having a melting point after recrystallization from ethanol-ether of 24925 1 4 EXAMPLE 3 Cis-l,2,3,3a,5,6,10b,11,12,12Zz decahydro 1 ethynyl- 1,8 dihydroxy-IZu-methylbemo[a]cyclopenta[f]quinolizine hydrobromide A solution of 1.8 grams of cis octahydro 1 (m-rnethoxyphenethyl) 4a methyl 5 hydroxy 5 ethynyl- 2H l pyrindine 2 one in 200 ml. of benzene containing 3 ml. of phosphorous oxychloride is refluxed for 20 minutes. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in ml. of ethanol. To this solution is added 5 grams of potassium borohydride and the mixture is stirred for 2 hours. The mixture is concentrated to dryness and the residue is dissolved in water and acidified with dilute hydrochloride acid. The solution is made basic with 10% ammonium hydroxide solution and the precipitate is extracted with methylene chloride. Dry hydrogen bromide is passed into the solution and the solution then concentrated to dryness. The residue is recrystallized from ethanol to give cis-1,2,3,3a,5,6,10b,11,12,12a-decahydrol-ethynyl 1,8 dihydroxy 12a methylbenzo[a]cyclopenta[f]quinolizine hydrobromide as White crystals, melting point 240.2".

EXAMPLE 4 Cis 2,3,3a,5,6,12,12a octahydro 1 hydroxy 1 ethynyl 8 methoxy 12a methyl 1H benz0[a]cyclopentafi]quinolizinium perchlorate A solution of 0.25 g. of cis-octahydro-l-(m-methoxyphenethyl) 4a methyl 5 hydroxy 5 ethynyl 2H 1 pyrindine-2-one in 5 ml. of benzene is treated with 0.5

m1. of phosphorous oxychloride. The solution is refluxed for 20 minutes during which time a yellow oil precipitates.

The mixture is concentrated to dryness and the residue is dissolved in 25 ml. of water. The clear solution is treated with a 10% solution of perchloric acid until precipitation of the oil salt is complete. The oil is taken up in 2 ml. of ethanol and cooled to give cis-2,3,3a,5,6,l2,12a-octahydro- 1 ethynyl 8 methoxy-12a-methyl-1H-benzo[a]cyclopenta[f]quinolizinium perchlorate as olf-white crystals.

After recrystallization from ethanol-ether, the product melts at 99101.

EXAMPLE 5 Trans 2,3,3a,5,6,12,12a octahydro 1 hydroxy 1- ethynyl 8 methoxy 12a methyl 1H benzo [a] cyclopentafi] quinolizinium perchlorate In the same Way as described in Example 4, 0 .5 g. of trans octahydro 1 (m methoxyphenethyl) 4amethyl-5-hydroxy-5-ethynyl 2H-1-pyrindine-2-one in 10 ml. of benzene and 1.0 ml. of phosphorous oxychloride gives trans 2,3,3a,5,6,l2,'12a octahydro 1 hydroxy- 1 ethynyl 8 methoxy 12a methyl 1H benzo[a] cyclopenta[f] quinolizinium perchlorate as yellow crystals, melting point 235.7 after recrystallization from isop-ropanol-acetonitrile.

EXAMPLE 6 Cis 2,3,3a,5,6,12,12a octahydro 1 ethynyl 1,8 dihydroxy 12a methyl 1H rbenzo[a]cyclo penta[f] quinolizin'ium perchlorate In the same Way as described in Example 4, 0.45 g. of cis octahydro 1 (m hydroxyphenethyl) 4a methyl- S-hydroxy-S-ethynyl-ZHd-pyrindine-2-one in 20 ml. of benzene and 0.5 ml. of phosphorous oxychloride gives cis- 2,3,3a,5,6,12,12a octahydro 1 ethynyl 1,8 dihydroxy 12a methyl 1H benzo[a]cyclopenta[f]quinolizinium perchlorate as a pale yellow viscous oil.

It is understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of our invention.

Having described our invention, what we desire to secure by Letters Patent is:

1. A compound selected from the group consisting of those having the formula:

of hydrogen and acyl and R is a member of the group consisting of hydrogen, halogen, lower alkoxy, aryl and lower alkyl and n is an integer of 1 to 2.

2. Cis 2,3, 3a,5,6,12,*12a octahydro 1 hydroxy 1- ethynyl 8 methoxy 12a methyl 1H benzo[a] cyclopenta[f] quinolizinium perchlorate.

3. Trans 2,3,3a,5,6, 12,12a octahydro 1 hydroxy- 1 ethynyl 8 methoxy 12a methyl 1H benzo[a] cyclopentafi]quinolizinium perchlorate.

4. Cis 2,3,3a,5,6, 12,12a octahydro 1 ethynyl 1,8- dihydroxy 12a methyl 1H benzo[a]cyclopenta[f] quinolizinium perchlorate.

References Cited by the Examiner Meltzer et al.: Tetrahedron Letters No. 23, pp. 1581-4 (1963), Chem. Abstr. vol. 59, column 15 343e.

ALEX MAZEL, Primary Examiner.

DONALD G. DAUS, Assistant Examiner. 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THE FORMULA:
 2. CIS - 2,3,3A,5,6,12,12A - OCTAHYDRO - 1 - HYDROXY - 1ETHYNYL - 8 - METHOXY - 12A - METHYL - 1H - BENZO(A)CYCLOPENTAL(F)QUINOLIZINIUM PERCHLORATE. 